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Elucidating how ATR promotes genome stability independent of the DNA damage response pathway

Award Number: R35GM150648
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Elucidating how ATR promotes genome stability independent of the DNA damage response pathway - ABSTRACT Genome instability is generally deleterious to cell growth. Paradoxically, in cancer, it is associated with increased drug resistance, metastasis and immune evasion; all of which contribute to poor patient prognosis. The broader landscape of our research is to fully understand how the DNA damage response (DDR) pathway and mitotic machinery work in concert to promote faithful genome stability. A major component of the DDR pathway is Ataxia telangiectasia and Rad3 related (ATR) kinase. I previously discovered an unexpected, and novel DNA damage- independent, role for ATR kinase after mitotic entry. This newly revealed role for ATR is essential for genome stability. This unexpected role for ATR opened up many opportunities to understand cross-talk between the pathways that regulate genomic stability and is foundational to my lab. Our long-term goal is to make unique contributions by elucidating how the non-canonical roles of the proteins that make up the DDR pathway ensure genome stability. Our five-year goal is to further our understanding of the mechanisms by which ATR promotes genome stability outside of the DNA damage response pathway in both mitosis (program 1) and interphase (program 2). Our current understanding of the mitotic function of ATR is limited to our previous observations that ATR activates promotes proper Aurora B activity. This leaves a large gap of knowledge as to how ATR promotes proper chromosome segregation. We will explore the mitotic pathways that ATR regulates, focusing on putative direct substrates that we have identified (program 1). Additionally, our previous work uncovered two novel, DDR independent functions of ATR, which we aim to fully explore in this proposal (program 2). (1) ATR directly phosphorylates lamin A/C in interphase. This has prompted us to define the function of ATR on nuclear plasticity and nuclear envelope breakdown. (2) Basal ATR activity is necessary for proper centromere identity throughout interphase. We will focus on how basal ATR activity promotes proper centromere identity and function through its regulation of promyelocytic nuclear bodies. We expect that these projects will yield critical information on the role of ATR in mitosis and how it and the DNA damage response pathway promote faithful chromosome segregation independent of DNA damage and further our understanding of the mechanism that promote genome stability.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $418,750 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	3	5/14/2025	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2024 ( Subtotal = $418,750 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	2	5/21/2024	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2023 ( Subtotal = $418,750 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	7/19/2023	NEW	$418,750
														Subtotal = $418,750

Grand Total All Awards = $1,256,250

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Elucidating how ATR promotes genome stability independent of the DNA damage response pathway

Award Number: R35GM150648

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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